Previous work on this grant indicated that natural killer (NK) cells are heterogeneous and have a potentially important role to play in mediating rejection of virus infected cells and restricting metastases of tumor cells. The overall aim of this application is to provide insight into the nature and capability of various NK cell subsets; the means by which they discriminate between virus infected an uninfected cells, and between neoplastic and nonneoplastic cells; the mechanisms of regulation of NK activity of these sets; and ultimately their functional role of resistance to virus infection and tumor cells in vivo. Where appropriate we will attempt to develop continuous murine and human NK cell lines of vrious NK phenotypes, study their regulation by IFN and IL-2, and attempt to delineate which subsets produce interferon and the pathways of differentiation as determined by cell surface markers. For studies of the nature of target cell recognition we will use target cells infected by a variety of viruses and viral mutants, and target cells transformed with fragments of oncogenic viral DNA to establish the relationship between events in neoplastic transformation and recognition by NK cells. For studies of the role of NK cells in vivo, we will examine primary mouse and human tumors and metastases from the same individual for susceptibility to NK cells in both beige mice and nude mice immunosuppressed for NK activity and will characterize mechanism of resistance to the growth tumors and metastases by adoptive transfers with defined lymphocyte subpopulations. Possible defects in the functioning of the IFN-NK system in patients with putative persistent viral diseases, multiple sclerosis and systemic lupus erythematosus will be pursued.